Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14].[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O[Li].O.Cl>ClCCl>[CH2:16]([O:23][C:7]1[C:2]([F:1])=[C:3]([CH2:12][C:13](=[O:15])[CH3:14])[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: ClCCl
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Temperature: 105 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (2.5 g, 82% purity by HPLC analysis, 9.54 mmol) were added benzyl alcohol (2.5 mL) and LiOH.H2O (1.07 g, 25.58 mmol). The reaction mixture was then heated to 100-110° C. and stirred for 4 hours until HPLC analysis indicated complete reaction. After cooling to RT, the reaction mixture was diluted with dichloromethane (18 mL) and neutralized to pH 6-7 with 1 N HCl. The layers were separated and the organic phase was washed with brine and collected. With stirring, heptane (30-25 mL) was added to the organic solution whereupon crystallization was initiated. The resulting slurry was cooled to 0-5° C. and stirred for an additional 1 h. The slurry was then filtered and the filter cake was washed with heptane. The yellow-brown solids were then dried in vacuo at 50° C. for 12-15 h to afford of the desired compound (1.6 g) which was 95% pure by HPLC analysis. HPLC method: Column: YMC Pack Cyano 3 μm, 4.6×50 mm Solvent A: 0.05% TFA in MeOH:Water (20:80), Solvent B: 0.05% TFA in MeOH:water (20:80), Wavelength: 254 nm Flow Rate: 3 mL/min. Gradient Time: 3 min. Final % B: 100 Initial Hold: 0.5 min. Start % B: 0. Typical Retention Times: SM, 1.2 min; Product 2.2-2.3 min.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#N)=[C:4]([CH3:11])[CH:3]=1.[OH-:12].[Na+].C[OH:15]>>[Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]([OH:15])=[O:12])=[C:4]([CH3:11])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Br)cc(C)c1C#N
Reactant: [OH-]
Agent: [Na+]
Product: Cc1cc(Br)cc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Bromo-2,6-dimethylbenzonitrile (4.0 g, 19 mmol) was stirred in MeOH (100 mL) and 5N NaOH (100 mL) at 100° C. for 12 hours. The reaction was cooled to room temperature and partitioned between CH2Cl2 and water and the organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the resulting product was stirred in H2PO3 (20 mL) for 6 hours at 150° C. The reaction mixture was basified with 6M KOH, filtered and then acidified with 12M HCl. The reaction was partitioned between CH2Cl2 and water and the organic layer was dried over anhydrous Na2-SO4. The solvent was removed under reduced pressure to afford the product (2.81 g). 1H NMR (300 MHz, CDCl3): δ 7.22 (s, 2H), 6.17 (s, 1H), 5.67 (s, 1H), 2.36 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][N:14]=[C:15]([CH2:16]CO)[C:8]=23)=[C:4]([F:21])[CH:3]=1.FC1C=C[C:26]([N:29]2[C:34](=[O:35])[C:33]([C:36]([OH:38])=O)=[CH:32][CH:31]=N2)=CC=1.[C:39]([O-])(O)=O.[Na+]>>[F:21][C:4]1[CH:3]=[C:2]([NH:1][C:36]([C:33]2[C:34](=[O:35])[N:29]([CH3:26])[CH:39]=[CH:31][CH:32]=2)=[O:38])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([CH3:16])[C:8]=12
Reactant: Nc1ccc(Oc2ccnc3[nH]nc(CCO)c23)c(F)c1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: O=C([O-])O
Agent: [Na+]
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)c4cccn(C)c4=O)cc3F)c12
Yield: 64 %

Procedure:
Prepared by a 2-step process from 2-(4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)ethanol and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (prepared as in Example 19, Step C) according to the procedure described for Example 21, Steps A and B, except that the crude was treated with aqueous NaHCO3 solution. The crude was purified by silica gel flash column chromatography (4% MeOH in CH2Cl2) to afford 6.6 mg (64%) of the desired product. LRMS (ESI pos) m/e 505.2 (M+1). 1H NMR (400 MHz, CDCl3/CD3OD) δ 8.41 (d, 1H), 8.32 (d, 1H), 8.25 (d, 1H), 8.0 (dd, 1H), 7.64 (m, 2H), 7.46 (m, 1H), 7.33 (t, 1H), 7.28 (m, 2H), 6.26 (d, 1H), 4.06 (t, 2H), 3.38 (t, 2H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −112.4, −127.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33]>C1COCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28]([C:37]4[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(I)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(-c3ccc(C#N)cc3)cc2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[3-formyl-1-(4-iodophenyl)-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (294 mg, 0.553 mmol) and Pd(PPh3)4 (32 mg, 0.0277 mmol) are placed in a side-armed test tube and flushed with N2. Tetrahydrofuran (6.0 mL) and 1M aq potassium carbonate (0.6 mL) are added followed by a solution of 4-cyanobenzeneboronic acid (122 mg, 0.830 mmol) in THF (2.0 mL). After stirring at 70° C. for 8 hr the reaction is cooled, then dissolved in ethyl acetate, washed with water (2×10 mL), with brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography eluting with heptane-10 to 40% ethyl acetate. Product containing fractions are combined and concentrated to afford 4-[1-(4′-cyanobiphenyl-4-yl)-3-formyl-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid. TLC (heptane-30% ethyl acetate); RT=0.13; ESI/MS 451 [M-C(CH3)3]; NMR (CDCl3) 10.30 (1H, s); 8.28 (1H, d, J=9 Hz); 7.84 (6H, m); 7.55 (2H, d); 7.29 (3H, m); 3.34 (8H, m); 1.44 (9H, s).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]([F:28])([F:27])[C:23](OC)=[O:24].Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:23](=[O:24])[C:22]([F:28])([F:27])[F:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(F)(F)F
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: -40 °C

Procedure:
A solution of 91.2 ml (0.23 mol) of 2.5M n-butyllithium solution was added dropwise at -40° C. to a solution of 50.0 g (0.19 mol) of 4-bromophenol benzyl ether in 250 ml of tetrahydrofuran. The mixture was subsequently stirred for a short time at -40° C., then cooled to -78° C., and 34 g (0.27 mol) of methyl trifluoroacetate were added dropwise. The mixture was allowed to come to room temperature and then stirred at 0° C. for 3 hours. For working up, 120 ml of dilute hydrochloric acid were added dropwise, the mixture was diluted with toluene, and the organic phase was separated off, washed with water, dried and concentrated. A brown solid was obtained which was recrystallized from petroleum ether/ethyl acetate 10:1.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH2:31])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(=O)([O-])[O-].[K+].[K+].C1C(=O)N([O:45][C:46]([CH2:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=2)=O)C(=O)C1>O.CS(C)=O>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH:31][C:46](=[O:45])[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=1)([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](N)[C@H]1O
Reactant: O=C(CCc1ccc(O)cc1)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](NC(=O)CCc2ccc(O)cc2)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
3'-Amino-3'-deoxyadenosine 5'-triphosphate (6 mg, 11 mmol) and potassium carbonate (7.2 mg, 55 mmol.) were dissolved in 0.8 ml of water. 3-(4-Hydroxyphenyl) propionic acid N-hydroxysuccinimide ester (27 mg, 0.1 mmol) in 0.4 ml of DMSO was added at room temperature, and the mixture was stirred for 24 hours at room temperature. The product was purified by the procedure described for 3'-acetylamino-3'-deoxyadenosine 5'-triphosphate (above); t=14 min (4.3 mg obtained, 41% yield). UV: lmax =259 nm. High resolution MS for C19H24N6O14P3 : calcd. 653.0563, found 653.0596 (MH3-).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[O:18])[O:16][C:15](=[O:19])[NH:14][C:13]=2[CH:20]=1.IC>O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[O:18])[O:16][C:15](=[O:19])[N:14]([CH3:3])[C:13]=2[CH:20]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c(=O)oc(=O)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
Sodium hydride (0.47 g, 12 mmol) was added to a 3 neck 250 mL RBF under nitrogen and then washed with hexanes. Once the hexanes were decanted, N,N-dimethylformamide (20.0 mL, 11 mmol) was added. The resulting mixture was cooled to 0° C. using an ice-water bath, and then 7-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (2.7 g, 11 mmol) was added in one batch. After stirring at room temperature for 1 hour, iodomethane (0.70 mL, 11 mmol) was added dropwise to the yellow solution, and the reaction mixture was stirred for 16 hours. Water (50 mL) was added, and the resulting precipitate that formed was collected via filtration. The solid was washed with additional water (100 mL), followed by ether (100 mL). Drying in a vacuum oven overnight at 50° C. afforded the desired product as an off-white solid (2.1 g, 74% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]3[CH:27]=[CH:26][C:16]([CH2:17]P(=O)(OCC)OCC)=[CH:15][CH:14]=3)[N:12]=2)[CH:9]=1.[O:28]([CH2:36][CH2:37][O:38][C:39]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:40]=1[CH:41]=O)[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].CCOC(C)=O.CCCCCC>C1COCC1>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16](/[CH:17]=[CH:41]/[C:40]4[CH:43]=[CH:44][C:45]([N+:47]([O-:49])=[O:48])=[CH:46][C:39]=4[O:38][CH2:37][CH2:36][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:26][CH:27]=3)[N:12]=2)[CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc([N+](=O)[O-])ccc1C=O
Reactant: CCOP(=O)(Cc1ccc(-c2cn3cc(C)ccc3n2)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccc([N+](=O)[O-])cc4OCCO[Si](C)(C)C(C)(C)C)cc3)cn2c1
Yield: 64.3 %

Procedure:
Prepared as described in the Alkene Formation section using sodium hydride (40 mg, 60% dispersion in mineral oil, 1.00 mmol), diethyl [4-(6-methylimidazo[1,2-a]pyridin-2-yl)benzyl]phosphonate (0.300 g, 0.837 mmol) and 2-([2-tert-butyldimethylsiloxy]ethoxy)-4-nitrobenzaldehyde (0.272 g, 0.837 mmol) in dry THF (30 ml) to give the title compound (0.285 g, 64%) as an orange solid after work-up and flash chromatography (2:1 EtOAc/Hexane).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11](=[O:24])[C:12]3[C:17]([O:18][C:19]=2[C:20]=1[C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=[CH2:5].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[CH2:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11](=[O:24])[C:12]3[C:17]([O:18][C:19]=2[C:20]=1[C:21](=[O:23])[CH:22]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=[CH2:5]
Reactant: O=Cc1ccccc1
Reactant: C=CCOc1ccc2c(=O)c3ccccc3oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc2c(=O)c3ccccc3oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-allyloxy-4-acetylxanthen -9one (2.2 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2 g of product m.p. 150-152° C., 1H-NMR (CDCl3)δ:4.73-4.74 (m, 2H); 5.25-5.42 (m, 2H); 5.92-6.05 (m, 1H); 7.07 (d, 1H, J=8.9 Hz); 7.13 (d, 1H, J=16 Hz); 7.36-7.44 (m, 6H); 7.52-7.60(m, 2H); 8;31-8.36 (m, 1H); 8.43 (d, 1 H, J=8.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:24])([F:25])[F:23])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-({5-[(1H-indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.278 g, 0.49 mmol) in DCM (5 mL) was added TFA (3.0 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.32 g of crude product which was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22]([N:29]1[C:37]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=2[C:31]([CH2:38]O)=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)(Cl)Cl>[CH2:22]([N:29]1[C:37]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=2[C:31]([CH2:38][Br:20])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCc1nn(Cc2ccccc2)c2c1CCCC2
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nn(Cc2ccccc2)c2c1CCCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
To a stirring solution of 752 mg (2.87 mmol, 1.3 equiv) of triphenylphosphine in 10 mL of CCl4 at 0° C. is added 135 μL (2.63 mmol, 1.2 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 580 mg (2.39 mmol) of (4,5,6,7-Tetrahydro-1-benzyl-1H-indazol-3-yl) methanol in 3 mL of CCl4 is added over 2 min. The resulting solution is stirred 2.5 h at RT, and the solvent is removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 76 mg of the title compound as a clear oil: 1H NMR (CDCl3, 300 MHz) δ7.32-7.24 (m, 3H), 7.10 (m, 2H), 5.17 (s, 2H), 4.49 (s, 2H), 2.48 (m, 4H), 1.74 (m, 4H); low resolution MS (FAB)m/e 305 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2].[CH3:16][Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCCC1.CI.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH:12]([CH3:16])[C:11](=[O:15])[C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2c1CCCC2=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)c1csc2c1CCC(C)C2=O
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (the compound of Preparation Example 3) (1.0 g) in tetrahydrofuran (9 mL) was added dropwise 1.0M lithium hexamethyldisilazide-tetrahydrofuran solution (4.9 mL). After stirring at −70° C. for 15 minutes, methyl iodide (0.34 mL) was added and the solution was warmed to room temperature and was stirred for 30 minutes. After an aqueous solution of saturated ammonium chloride was added and a further dilution with water, extraction was carried out with ethyl acetate. After the organic layer was washed with saturated sodium chloride water and dried with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (426 mg) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[CH2:31]([N:33]1[C:37]([C@H:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[OH:43])=[CH:36][CH:35]=[N:34]1)[CH3:32].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:43][C@H:39]2[CH2:40][CH2:41][CH2:42][C@@H:38]2[C:37]2[N:33]([CH2:31][CH3:32])[N:34]=[CH:35][CH:36]=2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1F
Yield: 81.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide (200 mg, 0.455 mmol) prepared in Example 14b, (1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol (78.0 mg, 0.432 mmol) prepared in Example 37a, sodium hydride (63%; 24.7 mg, 0.648 mmol) and DMF (2.0 mL), to yield the title compound (210 mg, 81%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18](N)=[O:19].C(=O)(O)[O-:22].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([OH:19])=[O:22]
Reactant: O=C([O-])O
Reactant: NC(=O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Temperature: 90 °C
Yield: 35 %

Procedure:
A stirred suspension of compound (xv) in conc. sulfuric acid (5 mL) and water (5 mL) were heated to 90° C. After 2 h the reaction mixture was diluted with water, neutralized with sodium bicarbonate and extracted with EtOAc (3×15 mL). The organic layer was dried (Na2SO4) and concentrated to give 6-bromo-2-(4-fluorophenyl)-2H-indazole-3-carboxylic acid (xvi) (70 mg, 35%) as a white solid. ESI-MS m/z calculated for [M+H]+: 336.98; found: 336.80.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([Br:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[BrH:17].[CH2:10]([S:8][C:1](=[NH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=S)c1ccccc1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Product: Br
Product: N=C(SCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of thiobenzamide (0.307 g, 2.24 mmol) in CH2Cl2 (11 mL) was added benzyl bromide (0.26 mL, 2.19 mmol) and the resultant solution was heated to reflux for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The resultant yellow solid was dried under vacuum to provide S-benzylthiobenzimidate hydrobromide (0.573 g, 85%). 1H NMR (DMSO-d6) δ 4.76 (s, 2H), 7.34–7.44 (m, 3H), 7.51–7.54 (m, 2H), 7.61–7.66 (m, 2H), 7.78–7.83 (m, 1H), 7.88–7.91 (m, 2H), 11.92 (br s, 1H).
Reaction SMILES: CS(NC1C=CC=CC=1N1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:68])[C@H:39]([NH:48][C:49]([C@@H:51]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][N:52]2[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:50])[CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[CH2:34][CH2:33]1.N1C=CC=CC=1.[C:75]1([CH2:81][S:82](Cl)(=[O:84])=[O:83])[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C@@H:39]([NH:48][C:49]([C@@H:51]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][N:52]2[C:61]([O:63][C:64]([CH3:65])([CH3:67])[CH3:66])=[O:62])=[O:50])[C:38](=[O:68])[N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][S:82]([CH2:81][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)(=[O:84])=[O:83])[CH2:33][CH2:34]2)=[CH:46][CH:45]=1.[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][C@@H:39]([NH:48][C:49]([C@@H:51]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][NH:52]2)=[O:50])[C:38](=[O:68])[N:35]2[CH2:34][CH2:33][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][S:82]([CH2:81][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)(=[O:84])=[O:83])[CH2:37][CH2:36]2)=[CH:42][CH:43]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(=O)(=O)Cc2ccccc2)CC1
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(=O)(=O)Cc2ccccc2)CC1)[C@@H]1Cc2ccccc2CN1
Yield: 95.9 %

Procedure:
tert-Butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-{[benzylsulfonyl]amino}phenyl)piperazinyl]ethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared according to the procedure for Preparation III using tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperazinyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Preparation IX) (730 mg, 1.2 mmol), pyridine (100 μl, 1.2 mmol) and α-toluenesulfonyl chloride (240 mg, 1.2 mmol) (Aldrich). The crude material was purified by flash chromatography (SiO2 10% EtOAc in CH2Cl2) to afford the desired compound (387 mg). MS (ESI, pos. ion) m/z: 772 (M+H), (ESI, neg. ion) m/z: 770 (M−H). Calc'd for C41H46ClN5O6S: 772.35. Anal. Calcd for C41H46ClN5O6S-0.5 C4H8O2: C, 63.26; H, 6.17; N, 8.58; Cl, 4.34. Found C, 62.98; H, 6.09; N, 8.36.